Worldwide, neurodegenerative diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease while the average age of Americans is steadily increasing. Today, over 35 million Americans are over the age of 65. Within the next 30 years this number is likely to double, putting more and more people at increased risk of neurodegenerative disease. The underlying hypothesis of this study is that the microbubble parameters play a major role in dictating the blood-brain barrier (BBB) properties using Focused Ultrasound (FUS). Over the past funding period in mice in vivo, our group has demonstrated that the lipid-shelled monodisperse microbubbles of separate diameter ranges could be engineered and used for BBB opening. In this renewal study, the primary objective is thus to utilize the previously acquired knowledge on the importance of the microbubble parameters on the BBB opening in mice and investigate how it affects trans-BBB drug delivery in both mice and monkeys. Ideally, the microbubble can be tailored to the molecule to be delivered through the FUS-induced BBB opening, i.e., achieving the highest permeability and volume of diffusion for that molecule while excluding larger ones. The multi-disciplinary team assembled encompasses all critical specialty areas required, such as ultrasound and microbubble engineering as well as MRI, PET and fluorescence brain imaging, drug delivery, behavioral assessment and mouse model development as they pertain to neuroscience and neurology. The specific aims are thus to: 1) assess the role of the microbubble in trans-BBB drug delivery; 2) assess the role of the microbubble in the safety of BBB opening and 3) assess the role of the microbubble in drug delivery and safety in large animals. The role of the microbubble in drug delivery and safety will be defined in this study. This could allow for better control over the efficacy and safety of the technique through bubble optimization and customization to the drug to be delivered. Parkinson's disease will be targeted but the findings should pertain to all other CNS diseases.